Robin Roychaudhuri

Schizophrenia (SCZ) is a complex neuropsychiatric disorder characterized by disruptions in cognition, perception, and social behavior. While traditional research has focused on neurotransmitter dysregulation, growing evidence implicates altered lipid metabolism as a key contributor to the disease’s molecular pathology. Lipids are essential for maintaining neuronal membrane integrity, facilitating synaptic transmission, supporting myelination, and regulating neuroinflammation, all processes disrupted in SCZ. This review examines the molecular alterations in lipid pathways in SCZ, focusing on the dysregulated metabolism of phospholipids, sphingolipids, cholesterol, and polyunsaturated fatty acids (PUFAs). We highlight findings from genetic studies, neuroimaging, and patient-derived induced pluripotent stem cell (iPSC) models, which collectively provide a translational framework for studying lipid-related abnormalities. Evidence from postmortem brain tissue and peripheral samples consistently reveals altered lipid profiles in individuals with SCZ. Integrative models combining genetic risk variants with environmental stressors such as maternal immune activation and perinatal hypoxia offer deeper insights into how lipid dysregulation emerges during neurodevelopment and impairs neuronal function. From a clinical perspective, targeting lipid metabolism presents promising avenues for biomarker discovery, early diagnosis, and therapeutic innovation. Lipid-based interventions, including targeting of sphingolipid or phosphatidylinositol pathways, may be particularly beneficial for treatment-resistant cases. By integrating molecular lipidomics with patient-specific models and systems-level approaches, this review underscores the potential of lipid-focused strategies to advance our understanding of SCZ pathophysiology and guide the development of novel treatments.

Mammalian D‐Cysteine is racemized from L‐cysteine by serine racemase, a pyridoxal phosphate (PLP)‐dependent enzyme. Endogenous D‐Cysteine plays a role in neural development by inhibiting proliferation of neural progenitor cells (NPCs) via protein kinase B (AKT) signaling mediated by the FoxO family of transcription factors. D‐Cysteine binds to Myristoylated Alanine Rich C Kinase Substrate (MARCKS) and alters phosphorylation at Ser 159/163 and its translocation from the membrane. By racemizing serine and cysteine, mammalian serine racemase may play important roles in neural development highlighting its importance in psychiatric disorders.

The presence of endogenous d-stereoisomers of amino acids in mammals dispels a long-standing dogma about their existence. d-Serine and d-aspartate function as novel neurotransmitters in mammals. However, the stereoisomer with the fastest, spontaneous in vitro racemization rate, d-cysteine, has not been reported. We utilized a novel, stereospecific, bioluminescent assay to identify endogenous d-cysteine in substantial amounts in the eye, brain, and pancreas of mice. d-Cysteine is enriched in mice embryonic brains at day E9.5 (4.5 mM) and decreases progressively with development (μM levels). d-Cysteine is also present in significantly higher amounts in the human brain white matter compared with gray matter. In the luciferase assay, d-cysteine conjugates with cyano hydroxy benzothiazole in the presence of a base and reducing agent to form d-luciferin. d-Luciferin, subsequently, in the presence of firefly luciferase and ATP, emits bioluminescence proportional to the concentration of d-cysteine. The assay is stereospecific and allows the quantitative estimation of endogenous d-cysteine in tissues in addition to its specificity for d-cysteine. Future efforts aimed at bioluminescent in vivo imaging of d-cysteine may allow a more noninvasive means of its detection, thereby elucidating its function.

Summary: The adult subventricular zone is one of the two neurogenic niches that continuously produce newborn neurons. Here we show that serine racemase (SR), an enzyme that catalyzes the racemization of L-serine to D-serine and vice versa, affects neurogenesis in the adult SVZ by controlling de novo fatty acid synthesis. Complete and conditional deletion of SR in nestin precursor cells lead to diminished neurogenesis in the SVZ. Nestin-cre+ mice showed reduced expression of fatty acid synthase and its substrate malonyl CoA, which are involved in de novo fatty acid synthesis. Global lipidomic analyses revealed significant alterations in lipid subclasses in nestin-cre+ mice. Decrease in fatty acid synthesis was mediated by phospho acetyl CoA carboxylase that was AMPK independent. Both L and D serine treatment rescued defects in SVZ neurogenesis, proliferation and levels of malonyl CoA in vitro . Our work shows that SR affects adult neurogenesis in the SVZ via lipid metabolism.

D-amino acids are being recognized in mammals as important molecules with function. This is a first identification of endogenous D-cysteine in mammalian pancreas. D-cysteine is synthesized by serine racemase (SR) and SR ^−/− mice produce 6-10 fold higher levels of insulin in the pancreas and plasma including higher glycogen and ketone bodies in the liver. The excess insulin is stored as amyloid in secretory vesicles and exosomes. In glucose stimulated insulin secretion studies in mouse and human islets, equimolar amount of D-cysteine showed higher inhibition of insulin secretion compared to D-serine, another closely related stereoisomer synthesized by SR. In mouse models of diabetes (STZ and NOD) and human pancreas, the diabetic state showed increased expression of D-cysteine compared to D-serine followed by increased expression of SR. SR ^−/− mice show decreased cAMP in the pancreas followed by reduced phosphorylation of CREB (S133), lower DNA methyltransferase enzymatic and promoter activities resulting in decreased methylation of the Ins1 promoter. D-cysteine is efficiently metabolized by D-amino acid oxidase and transported by ASCT2 and Asc1. Dietary supplementation with methyl donors restored the high insulin levels and low DNMT enzymatic activity in SR ^−/− mice. Our data show that endogenous D-cysteine in the mammalian pancreas is a regulator of insulin secretion. Highlights: Serine Racemase also functions as a cysteine racemase. Lack of Serine Racemase results in significantly high levels of insulin in the pancreas, plasma and larger islets. D-cysteine shows greater inhibition of insulin secretion compared to D-serine. Endogenous D-cysteine signals via cyclic AMP that mediates downstream CREB-DNMT1 interaction. CREB-DNMT1 interaction results in hypomethylation of Ins1 promoter that can be rescued by high methyl donor dietary supplementation rescuing high insulin levels.

D‐amino acids are being recognized as functionally important molecules in mammals. We recently identified endogenous D‐cysteine in mammalian brain. D‐cysteine is present in neonatal brain in substantial amounts (mM) and decreases with postnatal development. D‐cysteine binds to MARCKS and a host of proteins implicated in cell division and neurodevelopmental disorders. D‐cysteine decreases phosphorylation of MARCKS in neural progenitor cells (NPCs) affecting its translocation. D‐cysteine controls NPC proliferation by inhibiting AKT signaling. Exogenous D‐cysteine inhibits AKT phosphorylation at Thr 308 and Ser 473 in NPCs. D‐cysteine treatment of NPCs led to 50% reduction in phosphorylation of Foxo1 at Ser 256 and Foxo3a at Ser 253. We hypothesize that in the developing brain endogenous D‐cysteine is as a physiologic regulator of NPC proliferation by inhibiting AKT signaling mediated by Foxo1 and Foxo3a. Endogenous D‐cysteine may regulate mammalian neurodevelopment with roles in schizophrenia and Alzheimer's disease (AD).

D-amino acids are increasingly recognized as important signaling molecules in the mammalian central nervous system. However, the D-stereoisomer of the amino acid with the fastest in vitro spontaneous racemization rate, cysteine, has not been examined in mammals. Using chiral high-performance liquid chromatography and an stereospecific luciferase assay, we identify endogenous D-cysteine in the mammalian brain. We identify serine racemase (SR), which generates the NMDA glutamate receptor co-agonist D-serine, as a candidate biosynthetic enzyme for D-cysteine. Levels of D-cysteine are enriched over twentyfold in the embryonic mouse brain compared to the adult. D-cysteine reduces the proliferation of cultured mouse embryonic neural progenitor cells (NPCs) by approximately 50%, effects not shared with D-serine or L-cysteine. The antiproliferative effect of D-cysteine is mediated by the transcription factors FoxO1 and FoxO3a. The selective influence of D-cysteine on NPC proliferation is reflected in overgrowth and aberrant lamination of the cerebral cortex in neonatal SR knockout mice. Finally, we perform an unbiased screen for D-cysteine-binding proteins in NPCs by immunoprecipitation with a D-cysteine-specific antibody followed by mass spectrometry. This approach identifies myristoylated alanine-rich C-kinase substrate (MARCKS) as a putative D-cysteine-binding protein. Together, these results establish endogenous mammalian D-cysteine and implicate it as a physiologic regulator of NPC homeostasis in the developing brain.